2V58

CRYSTAL STRUCTURE OF BIOTIN CARBOXYLASE FROM E.COLI IN COMPLEX WITH POTENT INHIBITOR 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

A Class of Selective Antibacterials Derived from a Protein Kinase Inhibitor Pharmacophore.

Miller, J.R.Dunham, S.Mochalkin, I.Banotai, C.Bowman, M.Buist, S.Dunkle, B.Hanna, D.Harwood, H.J.Huband, M.D.Karnovsky, A.Kuhn, M.Limberakis, C.Liu, J.Y.Mehrens, S.Mueller, W.T.Narasimhan, L.Ogden, A.Ohren, J.Prasad, J.V.Shelly, J.A.Skerlos, L.Sulavik, M.Thomas, V.H.Vanderroest, S.Wang, L.Wang, Z.Whitton, A.Zhu, T.Stover, C.K.

(2009) Proc Natl Acad Sci U S A 106: 1737

  • DOI: https://doi.org/10.1073/pnas.0811275106
  • Primary Citation of Related Structures:  
    2V58, 2V59, 2V5A

  • PubMed Abstract: 

    As the need for novel antibiotic classes to combat bacterial drug resistance increases, the paucity of leads resulting from target-based antibacterial screening of pharmaceutical compound libraries is of major concern. One explanation for this lack of success is that antibacterial screening efforts have not leveraged the eukaryotic bias resulting from more extensive chemistry efforts targeting eukaryotic gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on antibacterial target space resembling these eukaryotic targets, we used whole-cell screening to identify a series of antibacterial pyridopyrimidines derived from a protein kinase inhibitor pharmacophore. In bacteria, the pyridopyrimidines target the ATP-binding site of biotin carboxylase (BC), which catalyzes the first enzymatic step of fatty acid biosynthesis. These inhibitors are effective in vitro and in vivo against fastidious gram-negative pathogens including Haemophilus influenzae. Although the BC active site has architectural similarity to those of eukaryotic protein kinases, inhibitor binding to the BC ATP-binding site is distinct from the protein kinase-binding mode, such that the inhibitors are selective for bacterial BC. In summary, we have discovered a promising class of potent antibacterials with a previously undescribed mechanism of action. In consideration of the eukaryotic bias of pharmaceutical libraries, our findings also suggest that pursuit of a novel inhibitor leads for antibacterial targets with active-site structural similarity to known human targets will likely be more fruitful than the traditional focus on unique bacterial target space, particularly when structure-based and computational methodologies are applied to ensure bacterial selectivity.


  • Organizational Affiliation

    Pfizer, Inc., Ann Arbor, MI 48105, USA. richard.miller2@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BIOTIN CARBOXYLASE
A, B
449Escherichia coliMutation(s): 0 
EC: 6.3.4.14
UniProt
Find proteins for P24182 (Escherichia coli (strain K12))
Explore P24182 
Go to UniProtKB:  P24182
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24182
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
LZJ PDBBind:  2V58 Kd: 0.82 (nM) from 1 assay(s)
Binding MOAD:  2V58 Kd: 0.82 (nM) from 1 assay(s)
BindingDB:  2V58 IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.211α = 90
b = 106.609β = 90
c = 122.344γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-01-13
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description